The present invention relates to the treatment of cerebral palsy in a juvenile patient and in particular to the promotion of normal muscle growth in a juvenile patient suffering from dynamic contractures caused by cerebral palsy.
Cerebral palsy is a collective name given to a range of conditions caused by brain injury caused at or around the time of birth, or in the first year of an infant's life. The brain injury may be caused, for example, by trauma during delivery. It may also arise through such causes as trauma due to road traffic accidents or meningitis during the first year of life. It has been found that there is an increased risk of cerebral palsy in prematurely born babies and, as a result of the improvements in technology which enable premature babies to be kept alive from a much earlier age, the incidence of cerebral palsy in many countries is actually increasing rather than falling.
Although the brain injury causing cerebral palsy is a non-progressive injury, its effects may change as the sufferer grows older. The largest group of sufferers from cerebral palsy suffer from spastic cerebral palsy. Spastic cerebral palsy is characterized by dynamic contractures of the muscles which impair or inhibit completely the sufferer's ability to use his or her muscles. Moreover, muscle growth is impaired such that the longitudinal muscles become shorter relative to their associated bones as the infant grows older. Where the leg muscles are affected, the mobility of the sufferer can be severely reduced. Conventional attempts to cure this defect and to restore a measure of normal mobility typically have involved surgical intervention to alter the lengths of the tendons once the state has been reached at which the knee joint can no longer be straightened or the sufferer can only walk on tiptoe.
There remains a need for a treatment which allows the longitudinal muscles to grow normally, thereby removing, or at least minimizing the need to resort to surgical intervention. Moreover, there remains a need for a treatment which can augment surgical intervention to improve the mobility of the sufferer.
A bacterial toxin, botulinum toxin, has been used in the treatment of a number of conditions involving muscular spasm, for example a blepharospasm, spasmodic torticollis (cervical dystonia), oromandibular dystonia and spasmodic dysphonia (laryngeal dystonia). The toxin binds rapidly and strongly to presynaptic cholinergic nerve terminals and inhibits the exocytosis of acetylcholine by decreasing the frequency of acetylcholine release. This results in paralysis, and hence relaxation, of the muscle afflicted by spasm.
The term Botulinum toxin is used herein as a generic term embracing the family of toxins produced by the anaerobic bacterium Clostridium botulinum and, to date, seven immunologically distinct toxins have been identified. These have been given the designations A, B, C, D, E, F and G. For further information concerning the properties of the various botulinum toxins, reference is made to the article by Jankovic & Brin, The New England Journal of Medicine, pp 1186-1194, No. 17, 1991 and to the review by Charles L. Hatheway, Chapter 1 of the book entitled “Botulinum Neurotoxin and Tetanus Toxin” Ed. L. L. Simpson, published by Academic Press Inc., of San Diego, Calif. 1989, the disclosures of which are incorporated herein by reference.
The Jankovic and Brin article reviews the use of botulinum toxin type A by intramuscular injection to treat focal dystonias, strabismus, blepharospasm and other facial nerve disorders, including hemifacial disorders and use with regard to other spastic conditions is also reviewed. The Hatheway publication reviews the properties of botulinum toxin and tetanus toxin and the organisms which produce them, noting on page 5 that subcutaneous injection of the toxin has been carried out.
The neurotoxic component of botulinum toxin has a molecular weight of about 150 kilodaltons and is thought to comprise a short polypeptide chain of about 50 kD which is considered to be responsible for the toxic properties of the toxin, and a larger polypeptide chain of about 100 kD which is believed to be necessary to enable the toxin to penetrate the nerve. The “short” and “long” chains are linked together by means of disulphide bridges.
The neurotoxic polypeptide component is present in a complex with non-toxic proteins and haemagglutinins, the molecular weight of the complex being in the region of 900 kD.
Botulinum toxin is obtained commercially by establishing and growing cultures of C. botulinum in a fermenter and the harvesting and purifying the fermented mixture in accordance with known techniques.
The “A” form of botulinum toxin is currently available commercially from several sources, for example, from Porton Products Ltd., UK under the tradename “DYSPORT”, and from Allergan Inc., Irvine, Calif. under the trade name “OCULINUM.”